The broad objective of this application is to elucidate humoral mechanisms which link the heart and kidney in the control of sodium homeostasis with a specific focus upon the physiology and pathophysiology of the natriuretic peptides system (NPS) in cardiorenal regulation during the progression CHF. Based upon previous work, the NPS emerges as a unique endocrine system which consists of three structurally similar but genetically distinct peptides which share biological similarities but possess unique properties and roles. This system consists of ANP of myocardial cell origin which is the most immediately released peptide which possesses natriuretic, renin-inhibiting and vasodilating properties. BNP also of myocardial cell origin is released only after sustained cardiac volume and pressure overload and is more natriuretic and resistant to degradation by neutral endopeptidase (NEP). CNP is is produced by vascular endothelial and renal epithelial cells and functions as an autocrine and paracrine vasorelaxing factor. While CNP is synthesized in the kidney, its precise renal actions remain to be clarified. The working hypothesis is as follows: Activation of the NPS occurs with the onset of left ventricular dysfunction (LVD) and serves as a ~protective humoral response~ to preserve cardiorenal homeostasis. This humoral response mediates a state of asymptomatic left ventricular dysfunction (ALVD) by preserving sodium balance and inhibiting activation of the intrarenal renin- angiotensin system (RAS) which retards the progression to overt CHF. The transition of overt CHF is marked by the development of a renal resistance to the NPS which occurs via an increase in inatrarenal ANG II which disrupts renal NPS signal transduction. This renal resistance is reinforced by enhanced natriuretic peptide degradation by NEP. These alterations in renal responsiveness and natriuretic peptide degradation result in sodium retention and contribute to further left ventricular dysfunction (LVD). While dietary sodium restriction is employed as the first step in the treatment of CHF to limit sodium accumulation, we hypothesize that the resulting sodium deficit is a powerful activator of the RAS in early CHF which leads to premature renal resistance potentiating alterations in ventricular structure and function. Lastly, based upon previous studies, we propose to continue the design and synthesis of chimeric peptides of the NPS which possess unique vasodilating and natriuretic actions which may prove of therapeutic efficacy in cardiorenal disease states such as CHF.